The objective of this research is the development of new chemotherapeutic agents for the control of human oral plaque and periodontal diseases. This objective will be accomplished by the design and selection of agents from structural classes of currently known, clinically effective agents. Attention in this project is focused upon those agents which may act by inhibition of microbial growth. Agents with properties resulting in their retention in the oral cavity are favored. Two classes which have been selected for structural development are the bis-biguanides and the salicylanilides. Previous studies of bis-biguanides and preliminary work indicates that bis-biquanide agents superior to chlorhexidine or alexidine may be found among aliphatic derivatives with compact but highly lipophilic terminal groups. Bis-biguanides with benzylic and cyclic aliphatic terminal groups will be synthesized and evaluated for in vitro antimicrobial activity as well as antiplaque activity via a newly developed in vitro tooth slab assay. The microorganisms involved in these studies include Actinomyces viscosus, Actinomyces naeslandii, Streptococcus mutans, Streptococcus sanquis, Actinomyces Israelii, and Gram negative rods isolated from patients with juvenile periodontitis. Repetitive cycles of syntheses and evaluation are planned in order to optimize activity. These bis-biguanides will incorporate both conventional bridge moieties and more rigid bridges designed to increase binding of the agents to salivary proteins. The design and syntheses of salicylanilides and salicylanilide analogs will be undertaken to produce agents in this class of antibacterials with antiplaque properties superior to those of tribromsalan, a clinically effective antiplaque agent. A series of non-halogenated n-alkyl salicylanilides and salicylamides of amino-heterocycles will be prepared and evaluated for in vitro antimicrobial and antiplaque properties. Agents, in both classes, with optimal in vitro activities will be further evaluated in vivo for control of the development of gingivitis and periodontitis in animals.